Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

Abstract

NF‐κB activation through B cell receptor (BCR) ligation is critical for B cell development, survival and antigen‐mediated activation of B cells. CARD domain and MAGUK‐domain containing protein‐1 (CARMA1), recently identified adaptor molecule, has been shown to play an essential role in BCR‐induced NF‐κB activation. CARMA1‐deficient B cells fail to proliferate upon BCR stimulation, leading to defective humoral responses. Surprisingly, CARMA1‐deficient B cells are also defective in CD40‐induced proliferation. The mechanisms responsible for CD40‐induced proliferation defect have not yet been characterized. In this study, we show that signaling cascades activated by CD40 stimulation are largely unaffected in CARMA1‐deficient B cells. Instead, we have found that the defective proliferation of CARMA1‐deficient B cells is due to two events. First, CARMA1‐deficient B cells show defective cell‐cycle progression. Secondly, the numbers of marginal zone (MZ) B cells, which are the main responders upon CD40 stimulation, are greatly diminished in CARMA1‐deficient mice. Since B cell maturation requires basal signaling through BCR and NF‐κB activation, we propose that impaired BCR signaling in CARMA1‐deficient mice leads to defective maturation of MZ B cell population, which in turn, contributes to impaired proliferation upon CD40 stimulation.

Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling

“…As previously reported in Carma1 -/-mice 37,38 , Carma1 L815P mice showed reduced mature B220 þ IgD hi IgM lo follicular and B220 þ CD21 hi CD23 lo marginal zone B cells in the spleen compared with WT mice, and an almost complete absence of peritoneal IgM þ CD5 þ B-1 B cells in Carma1 L815P mice ( Fig. 4a; Supplementary Fig.…”

Roles of the NF- B Pathway in Lymphocyte Development and Function

“…Such a scenario would be consistent with the fact that components of the conventional BCR signaling path to NF-kB were required for MZB development (e.g., Carma1, Malt1, Bcl-10, TRAF6, and Tak1) (Thome 2004;Pappu and Lin 2006;Kobayashi et al 2009;Schuman et al 2009). …”

CARD9 versus CARMA1 in innate and adaptive immunity

“…CARMA1 and probably BCL10 control the BCR-mediated JNK activation [14], whereas MALT1 might be dispensable [13,15]. CD40-induced activation is also defective in splenic B cells with L-CBM deficiency [12,15,18], possibly owing to the defective development of marginal zone B cells, which are the main responding cells to CD40 stimulation [18].…”